Pharmacologically active agents may be administered systemically, such as orally or intravenously, or locally, such as topically or subcutaneously. In either instance, it is often desirable to deliver to the targeted location a dosage of these agents that is no greater than that which may be metabolized immediately, as dosages in excess thereof may be unusable and/or harmful. This has traditionally required administration of the agents at regular time intervals, which can be laborious and/or impractical and can also lead to errors in administration.
As an alternative, pharmacologically active agent delivery systems have been developed whereby the active agent is delivered (preferably in a consistent, sustained-release amount) over a period of time. Specifically with regard to locally administered agents, sustained-release has been accomplished by utilizing microparticles containing the active agent and one or more pharmacologically inactive materials. Microparticles can be divided into “microspheres” and “microcapsules,” which are different from each other. Microspheres usually refer to a monolithic type formulation in which the drug molecules are dispersed throughout a polymeric matrix. On the other hand, microcapsules refer to reservoir devices in which the drug core is surrounded by a continuous polymeric layer or shell. The drug core of a microcapsule may comprise the drug itself or a microsphere containing the drug.
The microparticles are delivered to the desired location and the active agent is released therefrom over an extended period of time. For ocular applications, the microparticles can be delivered, for example, by injection to the posterior segment of the eye using a designed cannula, or otherwise introduced as implants.
Release of the active agent from microspheres may involve melting, solvation, and/or biodegradation of the polymer matrix. In the case of microcapsules, the active agent must penetrate the shell to reach the target location. This may be accomplished by mechanical rupture, melting, dissolution, ablation, and/or biodegradation of the shell and/or diffusion of the active agent through the shell.
In particular, biodegradable materials, such as polymers, that form a matrix with and/or encapsulate the pharmaceutically active agents, can be employed as a sustained delivery system. By biodegradable, it is meant that the materials are degraded or broken down under physiological conditions in the body such that the degradation products are excretable or absorbable by the body. The use of biodegradable polymers can provide a sustained release of an active agent by utilizing the biodegradability of the polymer to control the release of the active agent thereby providing a more consistent, sustained level of delivery.
The prior art discloses several methods of producing microparticles, including by solvent extraction, low-temperature casting, coacervation, hot melting, interfacial cross-linking, interfacial polymerization, spray drying, supercritical fluid expansion, supercritical fluid antisolvent crystallization, and solvent evaporation. Solvent extraction involves the use of organic solvents to dissolve water-insoluble polymers. A drug in soluble or dispersed form is added to the polymer solution, and the mixture is then emulsified in an aqueous phase containing a surface-active agent. The organic solvent diffuses into the water phase facilitating precipitation of solid polymer microspheres. An example of this technology may be found in U.S. Pat. No. 4,389,330 (issued to Tice, et al.).
A process known as low-temperature casting has been utilized to produce microparticles. In this process, which is described in U.S. Pat. No. 5,019,400 (issued to Gombotz, et al.), a polymer is dissolved in a solvent together with an active agent that can be either dissolved in the solvent or dispersed in the solvent in the form of microparticles. The polymer/active agent mixture is atomized into a vessel containing a liquid non-solvent, and overlayed with a liquefied gas, at a temperature below the freezing point of the polymer/active agent solution. The cold liquefied gas or liquid immediately freezes the polymer droplets. As the droplets and non-solvent for the polymer are warmed, the solvent in the droplets thaws and is extracted into the non-solvent, resulting in hardened microspheres.
Coacervation is based on salting out or phase separation from a homogeneous polymer solution of hydrophilic polymers into small droplets of a polymer-rich, second liquid phase. When an aqueous polymer solution is partially dehydrated or desolvated by adding a strongly hydrophilic substance or a water-miscible, non-solvent, the water-soluble polymer is concentrated in water to form the polymer-rich phase. This is known as “simple” coacervation. If water-insoluble drug particles are present as a suspension or as an emulsion, the polymer-rich phase is formed on the drug particle surface to form a capsule under suitable conditions. In “complex” coacervation, the polymer-rich complex (coacervate) phase is induced by interaction between two dispersed hydrophilic polymers (colloids) of opposite electric charges. This process is described in numerous patents, including U.S. Pat. No. 2,800,457 (issued to Green, et al.).
A hot melt or congealing process has been described wherein an active agent is mixed with a polymer, which is melted at high temperatures. The admixture is then transferred to a centrifugal atomizer and the formed droplets cooled and collected. This process is described in U.S. Pat. No. 3,080,293 (issued to Koff). Alternatively, as described in U.S. Pat. No. 4,898,734 (issued to Mathiowitz, et al.), the active agent is mixed with the melted polymer, and the molten mixture is suspended in a non-miscible solvent, heated above the melting point of the polymer, and stirred continuously. Once the emulsion is stabilized, it is cooled until the core material solidifies.
Interfacial cross-linking may be employed if the polymer possesses functional groups that can be cross-linked by ions or multi-functional molecules. As described in U.S. Pat. No. 4,138,362, (issued to Vassiliades, et al.), for example, producing microparticles by interfacial cross-linking involves mixing a water-immiscible, oily material containing an oil-soluble, polyfunctional cross-linking agent, and an aqueous solution of a polymeric emulsifying agent. An oil-in-water emulsion is formed containing the polyfunctional cross-linking agent dispersed in the form of microscopic emulsion droplets in the aqueous continuous phase containing the emulsifying agent, and a solid capsule wall is formed by the cross-linking of the emulsifying agent by the polyfunctional cross-linking agent.
Interfacial polymerization requires monomers that can be polymerized at the interface of two immiscible substances to form a membrane. U.S. Pat. No. 4,119,565 (issued to Baatz, et al.) discloses a process for encapsulation wherein a poly-functional compound is dissolved in a core material, or in an inert solvent or solvent mixture, and subsequently mixed with the core material. This homogeneous mixture is then introduced into a liquid phase immiscible therewith, for example water, which contains a material that catalyzes polymerization of the poly-functional compound.
Another known microparticle process is spray drying, wherein a solid forming material, such as a polymer, which is intended to form the bulk of the particle, is dissolved in an appropriate solvent to form a solution. Alternatively, the material can be suspended or emulsified in a non-solvent to form a suspension or emulsion. An active agent is then added and the solution is atomized to form a fine mist of droplets. The droplets then enter a drying chamber where they contact a drying gas. The solvent is evaporated from the droplets into the drying gas to solidify the droplets, thereby forming particles. The particles are then separated from the drying gas and collected. This process is described in U.S. Pat. No. 6,308,434 (issued to Chickering, III, et al.), and references disclosed therein.
Microparticle formation using supercritical fluid expansion involves the rapid dissolving of a solid material into a supercritical fluid solution at an elevated pressure and then rapidly expanding the solution into a region of relatively low pressure. This produces a molecular spray that is discharged into a collection chamber. The solvent is vaporized and pumped away, and the particles are collected. An example of this process is described in U.S. Pat. No. 4,734,451 (issued to Smith).
Supercritical antisolvent crystallization, as disclosed in U.S. Pat. No. 6,461,642 (issued to Bisrat, et al.), involves dissolving the active agent, and, optionally, one or more carrier materials in a first solvent, introducing the solution and a supercritical or subcritical fluid into an apparatus, wherein the fluid contains an anti-solvent (such as carbon dioxide) and a second solvent. The essentially crystalline particles formed contain the active agent in a solvated form. The particles may be further dried using a dry anti-solvent in a supercritical or subcritical state.
One widely utilized process employs solvent evaporation to form microparticles containing active agents. In a solvent evaporation process, the active agent and matrix material are dissolved in a volatile organic solvent that is ultimately removed by raising the temperature and/or lowering the pressure. The most widely utilized apparatus for forming microparticles via solvent evaporation incorporates a rotating device, often referred to as a spinning disk. The spinning disk process was originally described in U.S. Pat. No. 3,015,128, (issued on Jan. 2, 1962 to G. R. Somerville, Jr.), the disclosure of which that is germane to the spinning disk process is hereby incorporated by reference in its entirety to the extent not inconsistent with the disclosures in this Application.
Since the advent of the spinning disk technology, numerous modifications of the method and apparatus have been introduced; however, various problems associated therewith have not been alleviated. For example, broad particle size distributions are often obtained. Importantly, the narrower the particle size distribution, the more calculable and repeatable the dosage of active agents. In addition, “pure” coating material particles (placebo particles) are produced. This results in dosage dilution if the placebo particles are administered, or additional manufacturing costs if the placebo particles have to be separated from the active agent-containing microparticles. Furthermore, agglomeration of microparticles occurs, which further affects particle size distribution. What is needed is an apparatus and method for producing microparticles having narrow particle size distribution, reduced placebo formation, decreased agglomeration of particles, and improved product yield.